Feeding Rhythm-Induced Hypothalamic Agouti-Related Protein Elevation via Glucocorticoids Leads to Insulin Resistance in Skeletal Muscle.

Tetsuya Shiuchi,Sachiko Chikahisa,Noriyuki Shimizu,Hiroyoshi Séi,Airi Otsuka

doi:10.3390/ijms221910831

Abstract

Circadian phase shifts in peripheral clocks induced by changes in feeding rhythm often result in insulin resistance. However, whether the hypothalamic control system for energy metabolism is involved in the feeding rhythm-related development of insulin resistance is unknown. Here, we show the physiological significance and mechanism of the involvement of the agouti-related protein (AgRP) in evening feeding-associated alterations in insulin sensitivity. Evening feeding during the active dark period increased hypothalamic AgRP expression and skeletal muscle insulin resistance in mice. Inhibiting AgRP expression by administering an antisense oligo or a glucocorticoid receptor antagonist mitigated these effects. AgRP-producing neuron-specific glucocorticoid receptor-knockout (AgRP-GR-KO) mice had normal skeletal muscle insulin sensitivity even under evening feeding schedules. Hepatic vagotomy enhanced AgRP expression in the hypothalamus even during ad-lib feeding in wild-type mice but not in AgRP-GR-KO mice. The findings of this study indicate that feeding in the late active period may affect hypothalamic AgRP expression via glucocorticoids and induce skeletal muscle insulin resistance.

Highlights

Lifestyle-related diseases have been linked to obesity, type 2 diabetes, lipodystrophy, heart disease, and cancer, and have become one of the most serious health problems of our time
Evening-Type Feeding Rhythm Leads to Skeletal Muscle Insulin Resistance
In the Evening group, the respiratory quotient (RQ) was decreased within a day, while VO2 reductions were reversed (Figure 4F and G). These findings suggest that hypothalamic agouti-related protein (AgRP) was responsible for the evening feeding schedule-induced insulin resistance in skeletal muscle

Summary

Introduction

Lifestyle-related diseases have been linked to obesity, type 2 diabetes, lipodystrophy, heart disease, and cancer, and have become one of the most serious health problems of our time. The disruption of circadian oscillator components in the suprachiasmatic nucleus of the hypothalamus, which is master regulator of circadian rhythm in mammal, causes internal desynchronization in rodents and is considered a risk factor for metabolic disorders including obesity and diabetes. Shifts in hepatic clock gene expression patterns disturb feeding rhythms, contributing to changes in hepatic lipid metabolism and consequent whole-body insulin resistance. The feeding rhythm is stronger than habitual exercise for the prevention of diet-induced obesity [12]. These observations indicate that feeding schedules affect both metabolic states and circadian rhythms in rodents, but it remains unknown whether feeding rhythms influence the hypothalamic control system for energy metabolism

Objectives

Methods

Results